AMP-activated protein kinase (AMPK) functions to maintain cellular energy homeostasis. This function is due to the exquisite sensitivity of AMPK to changes in intracellular AMP/ATP and the ability of AMPK to phosphorylate a number of metabolic enzymes involved in biosynthetic pathways that consume ATP or in catabolic pathways that generate ATP. Thus, activation of AMPK under stress conditions will switch off energy-consuming pathways and switch on ATP production pathways, and thereby restoring cellular energy homeostasis. Our studies in the previous funding period showed that AMPK activity was increased in hearts with pressure overload hypertrophy in response to decreased energy reserve. Activation of AMPK contributed to increased glucose uptake and glycolysis in hypertrophied hearts, an important compensatory response for maintaining energy supply for overloaded hearts. While these findings support the classic paradigm of AMPK function, recent advances in the field suggest that the role of AMPK is not limited to the functional regulation of metabolic fluxes;AMPK signaling also modulates multiple biological pathways, such as protein synthesis and mitochondria biogenesis. Thus, a new paradigm is emerging that AMPK serves as a checkpoint to sustain energy balance by modulating biological responses to environmental changes. Based on these exciting observations we propose a novel role of AMPK in the development of cardiac hypertrophy and its transition to heart failure, i.e. AMPK signaling is a critical mechanism that sustains adaptive remodeling of the heart in response to chronic stress. To test our hypothesis, we have generated transgenic mice with cardiac-specific overexpression of a dominant negative mutant of the alpha2 catalytic subunit of AMPK (dnAMPK) and have confirmed that activation of AMPK is substantially blunted in these hearts. By applying multi-nuclear NMR spectroscopic techniques to assess myocardial energy metabolism in combination with other biochemical and molecular approaches, we will test the hypothesis that activation of AMPK during chronic pressure overload improves mitochondrial capacity for oxidative metabolism and modulates cardiac hypertrophy, and thereby sustaining energy balance and protecting against maladaption in the mouse model. Results from this study will advance the knowledge of cardiac hypertrophy and heart failure. It will also provide a basis for clinical application of metabolic intervention as a therapeutic strategy.